Therapeutic compositions



Patented Feb. 10, 1942 THERAPEUTIC COMPOSITIONS Robert S. Shelton, Mariemont, Ohio, assignor to Win. S. .Merrell Company, Reading, Ohio, a

- corporation of Delaware Application October 14, 1938,

No Drawing.

Serial No. 234,895

8 Claims.

This invention relates to improvements in the production of halogenated esters of vegetable fatty acids. It includes new halogenated esters as well as processes by which they are advantageously produced.

Halogenated vegetable oils, such as iodized or brominated oils, are usedas contrast media for roentgenographic. (X-ray) work.. For such purposes, the oils are injected into the body cavities, such as the lungs, sinuses, etc. As the halogenated oils are opaque to Roentgen or vX-rays, they permit the taking of shadow pictures. Brominated vegetable oils, besides being useful for X-ray diagnostic work, are useful for the treatment of chronic bronchitis, certain types of asthma, and in place of bromides as sedatives acting gradually and over along period of time. H

The new halogenated esters of vegetable oil fatty acids of the present invention are useful for much the same, purposes as the previously known brominated vegetable oils but have important advantages, including greatly increased stability as compared with the previously known brominated oils. As it is important that haloenated oils and the like, when used, be free from any appreciable amount of free halogen or free acid, the increased stability of the new products of this invention makes them particularly advantageous for therapeutic and-diagnostic use.

In accordance with the present invention, nondrying vegetable oils, containing, in combined form, a substantial proportion of unsaturated fatty acids, such assunflower seed oil, corn oil,

tion of bromo-chloro compounds, containing both bromine and chlorine in organic combination.

' By causing the esters of thefatty acids of such\ oils to combine with chlorine as well as bromine, a brominated oil or ester having greater stability than previously known. brominated oils is produced.

The proportions of bromine and chlorine which may be eoinb1ned with the oils or est rs in,pre-- paring the new products of the prese invention may be varied over a-re1atively wide range, with the production of products having someuse as sedatives in place of .bromides or the like, the amount of combined bromine may be around 10% or somewhat less, and the amount 01' combined chlorine a small fraction, for example is, of the amount of combined bromine. For other purposes, particularly-for use as a contrastmedium in bronchography, bronchiectasis, or for myelography, oils or V esters of higher specific gravity, containing, forexample, around 35% or somewhat more bromine and 3% or somewhat more chlorine inorganic combination are used with advantage. M

In general, the halogenated glycerides are more viscous and of greater specific gravity than the halogenated esters, such as the, bromochloro ethyi esters, and hence have advantages where high viscosity is desired, for example,in making X-ray pictures of the lungs. The. bromo chloro ethyl esters of the sunflower seed, walnut seed, corn or soya bean oil fatty acids have an unusually low viscosity, less than that of water,

approaching the viscosity of body fluids, and hence have important advantages for use where a halogenated oil of 108V viscosity is desired.

. The invention will be further illustrated by the following specific examples, but it is not limited of the mixture at about 0 to 5 C. The chlorostirring is continued for another hour.

bromine mixture is added over a period of eight hours or more. When this addition is completed,

The reaction product is then poured into 2000 parts of ethylene dichloride and is washed repeatedly with water until the washings no longer give any reactionjwith brom phenol blue. The sclutionis themseparatedirom the water and dried over anhydrous sodium sulfate. After drying, the solvent isre noved by distillation under reduced what difierent characteristics, depending "upon 4 the amount of combined halogen, but all having increased stability as compared with simple brominated Oils or esters of comparable bromine" pressure while maintaining the temperature be-,

to abso'rb any hydrohalide whichmay .be liberatedduring storage. For storage and distribution theifinal product is bottled under nitrogen content. Where'the products are intended for in amber bottles. v

This product is fairly viscous, is pale yellow in color and has an oleaginous taste and odor. It is soluble in ether, benzene and chloroform but is insoluble in alcohol and water. It contains an extremely small amount of free acid and free halogen. Treatment of the oil with concentrated sulfuric acid liberates the chlorine and bromine.

The product is quite stable. It is an excellent contrast medium for roentgenographic work and is useful for other therapeutic purposes.

Example 2.-1000 parts of sunflower seed oil are placed in a suitable vessel equipped with a reflux condenser and a mixture of 2000 parts of ethyl alcohol and 50 parts of concentrated sulfuric acid are added. The mixture is refluxed for 15 hours on a steam bath. On standing, the reaction mixture separates into two layers. The oily layer is decanted and is repeatedly washed with saturated salt solution until the washings no longer give an acid reaction with Congo red paper. The ester so produced is dried for two days over anhydrous sodium sulfate and is finally purified by distillation under reduced pressure. The pressure used in the distillation should be less than 10 mm. to prevent decomposition. These ethyl esters boil at 180-230 C./2-3 mm. The product is a very light colored, oily liquid.

2000 parts of the ethyl esters of sunflower seed oil fatty acids, produced as described, are placed in a vessel provided with a mechanical stirrer and two dropping funnels. 1000 parts of dry ether are added and-the mixture iscooled to about 5 C. by the use. of an ice bath. The stirrer is started, and 1000 parts of a chloro-bromlne mixture chlorine in bromine) are added through the dropping devices slowly, with as good dispersion of the halogen throughjhe oil as possible. The temperature of the reaction mixture should not be allowed to exceed 10 C., and the addition of the 1000 parts of the chloro-bromine mixture should require six hours or more. After all of the halogen has been added, stirring is continued about one hour longer. The reaction mixture then poured into 2000 parts of ethylene dichloride and is repeatedly washed with water until the washings no longer give a reaction with brom phenol blue. The product is then dried over anhydrous sodium sulfate, filtered, and the solvent is distilled off under a reduced pressure, with the temperature advantageously maintained below 40 C. After the removal of all of the solvent, the oil is placed in amber bottles under nitrogen.

The product has an unusually low viscosity, less than that of water, approaching the viscosity of the body fluids. It has a specific gravity of about 1.15. It contains extremely little free acid or free halogen and is non-irritating to mucous membranes. It contains about 30% of bromine and 3% of chlorine in organic combination. It is a pale yellow color, has an oleaginous taste, is soluble in benzene, ether and chloroform, slight- 1y solubl in alcohol and insoluble in water.

The product is an excellent contrast medium for roentgenographic work, and because of its low viscosity, is of value for introduction into body cavities difflcultly injectable by oils of relatively high viscosity.

The proportions of combined bromine and chlorine in the new products may be varied over a relatively wide range, depending upon the properties desired. In the examples given, products containing 30% or more of combined halogen (10% chlorine on the bromine) are described. Other useful products may be produced in substantially the same way, with the use of different proportions of ester and halogen, or different proportions of bromine and chlorine, such products having the same improved stability. For example, the products may contain from 10% or less combined bromine to 35% or more combined bromine, and from /g% or less combined chlorine to 3 to 5% or even more combined chlorine' The viscosity, opacity'to X-rays, therapeutic properties, etc., will naturally vary with the content of combined halogen; but all will have increased stability because of the inclusion of combined chlorine. Also, the bromine and chlorine need not be added simultaneously or in admixture, but may be reacted separately with the esters, with the production of products containing both combined chlorine and bromine, although the simultaneous addition of the chlorine and bromine is advantageous.

It will, of course, be understood that other oils than sunflower seed oils, such as other non-drying oils containing a substantial proportion of esters derived from unsaturated fatty acids. including corn oil, walnut oil, soya bean oil, sesame oil, etc., or the alkyl esters of the fatty acids of such vegetable oils. may be used with the production of corresponding halogenated products. However, products derived from sunflower seed oil and the ethyl esters of sunflower seed oil fatty acids have important advantages over products derived from such other oils or esters.

I claim:

1. As new products, alkyl esters of fatty acids of non-drying vegetable -oils organically combined with bromine and chlorine, the amount of combined chlorine not exceeding 10% of the amount of combined bromine.

2. Asnew products. non-dry vegetable Oils organically combined with bromine and chlorine, the amount of combined chlorine not exceeding 10% of the amount of combined bromine.

3. As new products, ethyl esters of fatty acids of non-drying vegetable oils combined with bromine and chlorine, the amount of combined chlorine not exceeding 10% of the amount of combined bromine.

4. As new products, non-drying vegetable oils organically combined with about 30% bromine and about 3% chlorine.

5. Sunflower seed oil organically combined with bromine and chlorine, the amount of combined chlorine not exceeding 10% of the amount of combined bromine.

6. Ethyl esters of the fatty acids of sunflower seed oil organically combined with chlorine and bromine, the amount of. combined chlorine not exceeding 10% of the amount of combined bromine. 

